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(Circulation. 2004;110:3062-3067.)
© 2004 American Heart Association, Inc.

Coronary Heart Disease

Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice

Sven Wassmann, MD; Thomas Czech, MS; Martin van Eickels, MD; Ingrid Fleming, PhD; Michael Böhm, MD; Georg Nickenig, MD

From the Klinik für Innere Medizin III (S.W., T.C., M.B., G.N.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Aventis Pharma Deutschland (M.v.E.), Cardiovascular Disease Group, Frankfurt/Main, Germany; and Institut für Kardiovaskuläre Physiologie (I.F.), Johann W. Goethe-University, Frankfurt/Main, Germany.

Correspondence to Prof Georg Nickenig, Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany. E-mail nickenig{at}med-in.uni-sb.de

Received December 16, 2003; de novo received May 19, 2004; accepted June 10, 2004.

Background— Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis.

Methods and Results— Apolipoprotein E–deficient (ApoE^–/–) mice were crossed with AT1A receptor–deficient (AT1^–/–) mice to obtain homozygous double-knockout animals (ApoE^–/–-AT1^–/– mice). Wild-type (C57BL/6J), ApoE^–/–, AT1^–/–, and ApoE^–/–-AT1^–/– mice were fed a high-cholesterol diet for 7 weeks. In contrast to wild-type and AT1^–/– mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE^–/– mice. In the age-matched ApoE^–/–-AT1^–/– littermates, development of diet-induced endothelial dysfunction and atherosclerotic lesion formation was profoundly inhibited. Concomitantly, aortic release of superoxide radicals was increased 2-fold in ApoE^–/– mice compared with wild-type animals, whereas aortic superoxide production was normalized in ApoE^–/–-AT1^–/– mice (L-012 chemiluminescence). There were no significant differences in plasma cholesterol levels between ApoE^–/– and ApoE^–/–-AT1^–/– animals. Systolic blood pressure was significantly lower in ApoE^–/–-AT1^–/– animals than in ApoE^–/– mice (tail-cuff measurements). Oral treatment of ApoE^–/– mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function.

Conclusions— Genetic disruption of the AT1A receptor leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in ApoE^–/– mice irrespective of blood pressure and plasma cholesterol levels. These results indicate a fundamental role of AT1 receptor activation in atherogenesis.

Key Words: hypercholesterolemia • angiotensin • endothelium • atherosclerosis • free radicals

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